Luca Maccioni1, Axelle Loriot2,3, Joseph Dewulf4,5, Guido Bommer4, Yves Horsmans6, Nicolas Lanthier1,6, Isabelle Leclercq1, Bernd Schnabl7,8, Peter Stärkel1,6. 1. Institute of Experimental and Clinical Research, Laboratory of Hepato-Gastroenterology, UCLouvain, Université Catholique de Louvain, Brussels, Belgium. 2. Group of Genetics and Epigenetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium. 3. Group of Computational Biology and Bioinformatics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium. 4. de Duve Institute & WELBIO, UCLouvain, Bruxelles, Belgium. 5. Department of Laboratory Medicine, University Hospital St. Luc, UCLouvain, Bruxelles, Belgium. 6. Department of Hepato-gastroenterology, Cliniques Universitaires Saint-Luc, Brussels, Belgium. 7. Department of Medicine, University of California San Diego, La Jolla, California, USA. 8. Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA.
Abstract
BACKGROUND: Intestinal T cells are key in gut barrier function. Their role in early stages of alcohol-associated liver disease (ALD) remain unknown. AIM: To explore the links between intestinal T cells, microbial translocation and ALD METHODS: Patients with alcohol use disorder (AUD) following a rehabilitation programme were compared to subjects with non-alcoholic fatty liver disease (NAFLD) and healthy controls. Clinical and laboratory data (liver stiffness, controlled attenuation parameter, AST, ALT, K18-M65) served to identify AUD patients with isolated steatosis (minimal liver disease) or steatohepatitis/fibrosis (ALD). Serum microbial translocation markers were measured by ELISA, duodenal and plasma levels of sphingolipids by targeted LC-MS. T lymphocytes in duodenal biopsies were characterised by immunohistochemistry, flow cytometry and RNA sequencing on FACS-sorted cells. Mechanisms for T-cell alterations were assessed in vitro. RESULTS: Patients with ALD, but not those with minimal liver disease, showed reduced numbers of duodenal CD8+ T resident memory (TRM) cells compared to controls or patients with NAFLD. TRM transcriptomic analysis, in vitro analyses and pharmacological inhibition of cathepsin B confirmed TRM apoptosis driven by lysosomal membrane permeabilisation and cathepsin B release into the cytosol. Altered lipid metabolism and increased duodenal and plasma sphingolipids correlated with apoptosis. Dihydroceramide dose-dependently reduced viability of TRM. Duodenal TRM phenotypic changes, apoptosis and transcriptomic alterations correlated with increased levels of microbial translocation markers. Short-term abstinence did not reverse TRM cell death in patients with ALD. CONCLUSIONS: Duodenal CD8+ TRM apoptosis related to functional changes in lysosomes and lipid metabolism points to impaired gut adaptive immunity specifically in patients with AUD who developed early ALD.
BACKGROUND: Intestinal T cells are key in gut barrier function. Their role in early stages of alcohol-associated liver disease (ALD) remain unknown. AIM: To explore the links between intestinal T cells, microbial translocation and ALD METHODS: Patients with alcohol use disorder (AUD) following a rehabilitation programme were compared to subjects with non-alcoholic fatty liver disease (NAFLD) and healthy controls. Clinical and laboratory data (liver stiffness, controlled attenuation parameter, AST, ALT, K18-M65) served to identify AUD patients with isolated steatosis (minimal liver disease) or steatohepatitis/fibrosis (ALD). Serum microbial translocation markers were measured by ELISA, duodenal and plasma levels of sphingolipids by targeted LC-MS. T lymphocytes in duodenal biopsies were characterised by immunohistochemistry, flow cytometry and RNA sequencing on FACS-sorted cells. Mechanisms for T-cell alterations were assessed in vitro. RESULTS: Patients with ALD, but not those with minimal liver disease, showed reduced numbers of duodenal CD8+ T resident memory (TRM) cells compared to controls or patients with NAFLD. TRM transcriptomic analysis, in vitro analyses and pharmacological inhibition of cathepsin B confirmed TRM apoptosis driven by lysosomal membrane permeabilisation and cathepsin B release into the cytosol. Altered lipid metabolism and increased duodenal and plasma sphingolipids correlated with apoptosis. Dihydroceramide dose-dependently reduced viability of TRM. Duodenal TRM phenotypic changes, apoptosis and transcriptomic alterations correlated with increased levels of microbial translocation markers. Short-term abstinence did not reverse TRM cell death in patients with ALD. CONCLUSIONS: Duodenal CD8+ TRM apoptosis related to functional changes in lysosomes and lipid metabolism points to impaired gut adaptive immunity specifically in patients with AUD who developed early ALD.
Authors: Martin Trapecar; Shahzada Khan; Nadia R Roan; Tsui-Hua Chen; Sushama Telwatte; Monika Deswal; Montha Pao; Ma Somsouk; Steven G Deeks; Peter W Hunt; Steven Yukl; Shomyseh Sanjabi Journal: AIDS Res Hum Retroviruses Date: 2017-11 Impact factor: 2.205
Authors: Susan M Byrne; Anne Aucher; Syarifah Alyahya; Matthew Elder; Steven T Olson; Daniel M Davis; Philip G Ashton-Rickardt Journal: J Immunol Date: 2012-06-27 Impact factor: 5.422
Authors: Raquel Bartolomé-Casado; Ole J B Landsverk; Sudhir Kumar Chauhan; Lisa Richter; Danh Phung; Victor Greiff; Louise F Risnes; Ying Yao; Ralf S Neumann; Sheraz Yaqub; Ole Øyen; Rune Horneland; Einar Martin Aandahl; Vemund Paulsen; Ludvig M Sollid; Shuo-Wang Qiao; Espen S Baekkevold; Frode L Jahnsen Journal: J Exp Med Date: 2019-07-23 Impact factor: 14.307